The present invention relates to a method for preparing 5- and 6-benzyl functionalized quinoxalines.
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are numerically referenced in the following text and respectively grouped in the appended bibliography.
Substituted quinoxalines are important chemical intermediates for the preparation of pharmaceutical compounds, such as AMPHAKINE CX516 (copyright) [1-(quinoxalin-6-ylcarbonyl) piperidine]. Substituted quinoxalines are typically prepared by condensation of substituted ortho-diaminobenzenes with sodium glyoxal bisulfite as set out below (1): 
For example, 7-methoxy-5-aminoquinoxaline has been prepared by condensation of 3,4,5-triaminoanisole with sodium glyoxal bisulfite (2): 
Similarly, 7-methoxy-5-aminoquinoxaline and 7-methoxy-5-hydroxyamino-quinoxaline have been prepared from 3,5-dinitro-4-aminoanisole, which in turn was prepared by nitration of m-nitrobenzenesulfonyl-p-aminoanisole (3). 
Nevertheless, there are no reported procedures for preparing 6-hydroxymethylquinoxaline by condensation of 3,4-diaminohydroxymethylbenzene with sodium glyoxal bisulfite, presumably because such a method is not trivial and requires multiple steps. Because attempts to prepare 5- and 6-benzyl functionalized quinoxalines via a one-step selective reaction of the benzyl group were not successful, a two-step method to prepare 5- and 6-benzyl functionalized quinoxalines was developed.
In a first embodiment, the present invention pertains to a method for preparing a compound having Formula (I). 
In this first embodiment, the method comprises contacting an aqueous suspension of a compound having Formula (II) with a water-soluble nucleophile, N1, containing moiety Y; wherein X is chloro or bromo; R1 is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y is selected from the group consisting of xe2x80x94OR2, xe2x80x94NHR2, xe2x80x94NR2R3, xe2x80x94SR2, and xe2x80x94CN; and R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 4 carbon atoms.
In a second embodiment, the present invention pertains to a method for preparing a compound having Formula (I). 
In this second embodiment, the method comprises contacting a compound having Formula (II) with an organic solvent-soluble nucleophile, N2, containing moiety Y, in an inert polar organic solvent; wherein X is chloro or bromo; R1 is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y is selected from the group consisting of xe2x80x94OR2, xe2x80x94NHR2, xe2x80x94NR2R3, and xe2x80x94SR2; and R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 5 to 9 carbon atoms.
In a third embodiment, the present invention pertains to a method for preparing a compound having Formula (I). 
In this third embodiment, the method comprises contacting a compound having Formula (II) in an organic solvent with an aqueous solution of a water-soluble nucleophile, N1, containing moiety Y, in the presence of a phase transfer catalyst; wherein X is chloro or bromo; R1 is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y is selected from the group consisting of xe2x80x94OR2, xe2x80x94NHR2, xe2x80x94NR2R3, xe2x80x94SR2, and xe2x80x94CN; and R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 4 carbon atoms.
The present invention pertains to methods for preparing 5- and 6-benzyl functionalized quinoxalines. In a first embodiment, the method comprises contacting an aqueous suspension of a 5- and 6-halomethyl quinoxaline with a water-soluble nucleophile. In a second embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline with an organic solvent-soluble nucleophile in an inert polar organic solvent. In a third embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline in an organic solvent with an aqueous solution of a water-soluble nucleophile in the presence of a phase transfer catalyst.
The 5- and 6-halomethyl quinoxalines may be prepared from 5- and 6-methyl quinoxalines, which in turn may be prepared from ortho-diaminotoluenes, such as 2,3- and 3,4-diaminotoluene, by condensation with sodium glyoxal bisulfite. The preparation of ortho-diaminotoluenes is not trivial because the nitration of toluene yields mainly 2,4-dinitrotoluene, the precursor of 2,4-diaminotoluene (TDA, toluene-diamine), and only 4% or less of the ortho-isomers. However, 2,4-diaminotoluene is a bulk chemical, from which the ortho-diamine isomers are removed by distillation, and consequently uses for the ortho-diamine by-products are desired. The present invention provides a simple route to compounds such as 6-hydroxymethyl-quinoxaline by taking advantage of the availability of ortho-toluene diamine (OTD) using selective functionalization of the methyl group without affecting the aromatic rings.
Because attempts to prepare 5- and 6-benzyl functionalized quinoxalines via a one-step selective reaction of the benzyl group were not successful, a two-step method to prepare 5- and 6-benzyl functionalized quinoxalines was developed.
In the first step, a 5- or 6-benzyl-quinoxaline is halogenated to provide the corresponding 5- or 6-halomethyl-quinoxaline intermediate. 
X is halogen. The term xe2x80x9chalogenxe2x80x9d, as used herein, refers to fluorine, chlorine, bromine, and iodine. Preferred halogens are chlorine and bromine.
In the first step of the synthesis, a benzylic methyl heterocyclic compound and a halogenating agent, such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), are reacted in the presence of a radical initiator, such as benzoyl peroxide or azobisisobutyronitrile, in a suitable solvent, to form the respective 5- or 6-halomethyl quinoxaline (I). Suitable solvents may be selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1,xcex1,xcex1-trifluorotoluene and xcex1,xcex1,xcex1-trichlorotoluene. The method typically affords good yields of halomethyl-quinoxalines when [6QX]/[benzoyl peroxide]xe2x89xa640 while maintaining a temperature in the range of 60xc2x0 C. to 115xc2x0 C. for a period of 1 to 12 hours. Yields for benzylic brominations (conversions xe2x89xa795%, selectivities xe2x89xa797%) are in general better than for benzylic chlorinations (conversions 60%, selectivities xcx9c75-80%). The 5- or 6-halomethyl quinoxaline may be a 5-halomethyl quinoxaline or may be a 6-halomethyl quinoxaline. The halomethyl may be a chloromethyl or may be a bromomethyl.
This first step is more fully described in a copending patent application entitled xe2x80x9cMethod For Preparing Halomethyl Heterocyclic Compoundsxe2x80x9d filed by applicant concurrently with the present patent application and assigned to the assignee of this application, which is hereby incorporated by reference.
In the second step, the 5- or 6-halomethyl-quinoxaline intermediate (II) is contacted with a nucleophile to yield the corresponding 5- or 6-benzyl functionalized quinoxaline (I). 
In a first embodiment, the present invention pertains to a method for preparing a compound having Formula (I) which comprises contacting an aqueous suspension of a compound having Formula (II) with a water-soluble nucleophile, N1, containing moiety Y. 
In this first embodiment, the compound having Formula (I) may be: 
R1 may be selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms. Preferably, R1 is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 6 carbon atoms, more preferably R1 is selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 3 carbon atoms, and most preferably R1 is hydrogen.
The water-soluble nucleophiles, N1, containing moiety Y, which may be employed in the present invention may be any water-soluble nucleophile which is capable of selectively displacing the halogen group attached to the benzylic position of the heterocyclic compound in an aqueous suspension. The term xe2x80x9cwater-soluble nucleophilexe2x80x9d, as used herein, refers to a nucleophile that can be dissolved in water to yield a solution with a molarity equal to, or greater than, 0.01. Non-limiting illustrative water-soluble nucleophiles are those that contain a Y moiety, where Y may be selected from the group consisting of xe2x80x94OR2, xe2x80x94NHR2, xe2x80x94NR2R3, xe2x80x94SR2, and xe2x80x94CN. R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 4 carbon atoms. Preferably, R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 3 carbon atoms, more preferably R2 and R3 are independently selected from the group consisting of hydrogen and alkyl groups having from 1 to 2 carbon atoms, and most preferably R2 and R3 are hydrogen. Preferred water-soluble nucleophiles may be selected from the group consisting of alkali hydroxides and alkaline earth hydroxides. More preferred water-soluble nucleophiles may be selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide. Preferably, Y is hydroxy.
In a second embodiment, the invention is directed to a method for preparing a compound having Formula (I) which comprises contacting a compound having Formula (II) with an organic solvent-soluble nucleophile, N2, containing moiety Y, in an inert polar organic solvent. 
In this second embodiment, the compound having Formula (I) may be: 
The definition of X and R1 are as defined above.
The organic solvent-soluble nucleophiles which may be employed in the present invention may be any organic solvent-soluble nucleophile which is capable of selectively displacing the halogen group attached to the benzylic position of the heterocyclic compound in an inert polar organic solvent. The term xe2x80x9corganic solvent-soluble nucleophilexe2x80x9d, as used herein, refers to a nucleophile that can be dissolved in an organic solvent to yield a solution with a molarity equal to, or greater than, 0.01. Non-limiting illustrative organic solvent-soluble nucleophiles are those that contain a Y moiety, where Y may be selected from the group consisting of xe2x80x94OR2, xe2x80x94NHR2, xe2x80x94NR2R3, and xe2x80x94SR2. R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 5 to 9 carbon atoms. Preferably, R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 5 to 8 carbon atoms, more preferably R2 and R3 are independently selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 5 to 7 carbon atoms, and most preferably R2 and R3 are hydrogen. Preferred organic solvent-soluble nucleophiles may be selected from the group consisting of benzyltrimethyl ammonium hydroxide, tetrabutyl ammonium hydroxide, alkyl alcohols, aryl alcohols, alkylamines, arylamines, alkyl sulfides, aryl sulfides, and the salts thereof. More preferred organic solvent-soluble nucleophiles are benzyltrimethyl ammonium hydroxide and tetrabutyl ammonium hydroxide. Preferably, Y is hydroxy.
The inert polar organic solvents which may be employed in the present invention may be any inert polar organic solvent which is capable of dissolving the organic solvent-soluble nucleophile and the 5- or 6-halomethyl quinoxaline thereby permitting the selective displacement of the halogen group attached to the benzylic position of the heterocyclic compound. The term xe2x80x9cinert polar organic solventxe2x80x9d, as used herein, refers to an organic solvent that does not react with the organic solvent-soluble nucleophile or the 5- or 6-halomethyl quinoxaline and promotes a reaction between the organic solvent-soluble nucleophile and the 5- or 6-halomethyl quinoxaline. Non-limiting illustrative inert polar organic solvents may be selected from the group consisting of tetrahydrofuran, dioxane, 2-methoxyethyl ether, triethylene glycol dimethyl ether, dimethylsulfoxide (DMSO), methyl-tert-butyl ether (MTBE), and diethyl ether. Preferred inert polar organic solvents may be selected from the group consisting of tetrahydrofuran, dioxane, 2-methoxyethyl ether, triethylene glycol dimethyl ether, and dimethylsulfoxide. More preferred inert polar organic solvents may be selected from the group consisting of tetrahydrofuran, dioxane, and 2-methoxyethyl ether. Most preferred inert polar organic solvents are tetrahydrofuran and dioxane.
In a third embodiment, the invention is directed to a method for preparing a compound having Formula (I) which comprises contacting a compound having Formula (II) in an organic solvent with an aqueous solution of a water-soluble nucleophile, N1, containing moiety Y, in the presence of a phase transfer catalyst. 
In this third embodiment, the compound having Formula (I) may be: 
The definition of X, R1, and the water-soluble nucleophile are as defined above.
The organic solvents which may be employed in the present invention may be any organic solvent which is capable of dissolving the water-soluble nucleophile and the 5- or 6-halomethyl quinoxaline with the assistance of the phase transfer catalyst thereby permitting the selective displacement of the halogen group attached to the benzylic position of the heterocyclic compound. Non-limiting illustrative organic solvents may be selected from the group consisting of chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1,xcex1,xcex1-trichlorotoluene, fluorobenzene, difluorobenzenes, trifluorobenzenes, and xcex1,xcex1,xcex1-trifluorortoluene. Preferred organic solvents may be selected from the group consisting of chlorobenzene, dichlorobenzenes, fluorobenzene, and difluorobenzenes. More preferred organic solvents are chlorobenzene and dichlorobenzenes. The most preferred organic solvent is chlorobenzene.
The phase transfer catalysts which may be employed in the present invention may be any phase transfer catalyst which is capable of dissolving the water-soluble nucleophile and the 5- or 6-halomethyl quinoxaline in the organic phase thereby permitting the selective displacement of the halogen group attached to the benzylic position of the heterocyclic compound. The phase transfer catalyst is typically an organic salt (for example, tetraalkyl-ammonium salts, benzyltrimethylammonium salts, etc) that is soluble in both the aqueous phase and the organic phase. Non-limiting illustrative phase transfer catalysts may be selected from the group consisting of tetra-n-butyl-ammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium hydroxide, tetralkyl ammonium salts, tetraalkyl sulfonium salts, and cetyltrimethylammonium salts.
The 5- and 6-halomethyl quinoxalines and the nucleophiles may be reacted in relative amounts ranging from about 1:1 to about 1:100, and preferably from about 1:10 to about 1:30, respectively. The 5- and 6-halomethyl quinoxalines and the nucleophiles may be reacted at temperatures ranging from about 25xc2x0 C. to about 150xc2x0 C., preferably from about 25xc2x0 C. to about 100xc2x0 C., and at pressures ranging from ambient to about 100 psig, and preferably ambient.
The present invention is further illustrated by the following examples which are presented for purposes of demonstrating, but not limiting, the preparation of the compounds and compositions of this invention.